Aryl-substituted acetamide and pyrrolidin-2-one derivatives and their use for the treatment of seizures

ABSTRACT

Aryl-substituted acetamide and pyrrolidin-2-one (γ-butyrolactam) derivatives have useful activity in the inhibition, prevention, or treatment of seizures. The derivatives may be useful in the treatment of epilepsy, including medically refractory epilepsy, and nerve agent poisoning.

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/587,151, filed Nov. 16, 2017, entitled “Aryl-SubstitutedAcetamide and Pyrrolidin-2-one Derivatives and Their Use for theTreatment of Seizures,” the entire contents of which are herebyincorporated by reference.

BACKGROUND

This disclosure pertains to aryl-substituted acetamide andpyrrolidin-2-one (γ-butyrolactam) derivatives having useful anti-seizureactivity as applicable to epilepsy and nerve agent poisoning.

Epilepsy affects about 70 million people worldwide and thus is the mostcommon type of neurological disorder. Epileptic seizures result from theimbalance between the excitatory and inhibitory processes in the brain.Multiple proteins contribute to these processes, with the GABA_(A)receptors, NMDA receptors, and Na⁺ channels being regarded as the mostimportant. Despite many available antiepileptic drugs (AEDs), thepharmacotherapy of epilepsy remains to be hampered by two major issues.One issue is drug resistance (medically refractory epilepsy), when thecurrent first-line AEDs cannot control seizures in 25-41% of patients.The second issue are side effects that limit the usage of some effectiveAEDs. For example, AEDs that act primarily through the potentiation ofthe GABA_(A) receptor function frequently produce sedation or dizzinessand result in physical dependency (addiction). Seizures similar toepileptic ones are produced by chemical warfare nerve agents (such asSoman). Therefore, any treatments for epileptic seizures will also be ofvalue in treatment and prevention of nerve agent poisoning.

The antiepileptic activity of α-substituted acetamides and lactams hasbeen known for over six decades. The structural similarity ofanticonvulsant acetamides, lactams, cyclic imides, acylureas,hydantoins, and barbiturates and the consequent implication of a sharedmechanism of action and protein target has been fully realized only veryrecently. This realization triggered extensive studies (Krivoshein,2016a) that proposed the neuronal nicotinic acetylcholine receptors(nAChRs) in the brain as the shared targets of anticonvulsantα-substituted acetamides, lactams, and cyclic imides. FIG. 1 showsanticonvulsant α-substituted acetamides, lactams, cyclic imides, andstructurally related compounds. In the upper row are cyclic compoundsand in the lower row are the corresponding acyclic compounds(Krivoshein, 2016b).

Some aryl-containing acetamide and lactam derivatives have beenreported, including those with the structures shown below.

Azetidin-2-ones:

Reported compounds include 3,3-disubstituted azetidin-2-ones,derivatives with R₁=Ph (phenyl), R₁=Ph with ethoxy, alkyl, phenyl, andchloro substitution, R₂=methyl, ethyl, other alkyl, or phenyl, as wellas several N-alkyl derivatives (Testa et al., 1963; Fontanella, et al.,1973).

Pyrrolidin-2-ones:

Reported compounds include several 3- and 5-arylpyrrolidin-2-ones,including some N-alkyl substituted ones (Bavin, 1996; Bocchi et al.,1971; Marshall, 1958; Testa et al., 1966; Bertozzi et al., 1996; Brineet al., 1983).

Aryl-Substituted Acetamides:

Reported compounds include substitution around the benzene ring inphenylacetamide and N-unsubstituted and N-substituted amides (Easterlyet al., 1954; Kitamura et al., 2013; Clark et al., 1987; Shindikar etal., 2006). Reported compounds also include α-substitutedphenylacetamides (R₂═H), where R₁=methyl (Me), ethyl (Et), includingN-alkyl and N-aryl derivatives. Reported compounds also includeunsubstituted (R₁═R₂═H) and α-substituted (R₁=Et, Ph; R₂═H) derivativeswith various substituents around the benzene ring (hydroxy, amino,chloro, bromo, nitro, alkyl, alkoxy). Additional reported compoundsinclude disubstituted phenylacetamides where R₁═R₂=Me, and derivativeswith various substitution around the benzene ring (chloro, methyl,methoxy). (Pettersson, 1956; Chapman et al., 1957; Kitamura et al.,2013; Volwiler et al., 1936; Mijin et al., 2000; Roufos et al., 1996;Canonica et al., 1958; Koltunov et al., 2004).

Homologous Acetamides:

Reported compounds include those where R₁═R₂═H or Me, n=1: (additionalalkyl and aryl substitution, including chlorophenyl), and where R₁=Me,R₂=Et, n=1, and where R₁=ethyl, or other alkyl, R₂═H, n=1 to 6, and alsoN-alkyl and N,N-dialkyl derivatives. (Kushner et al., 1951; Koltunov etal., 2004; Chapman et al., 1957; Blicke et al., 1938).

Phenylacetamide with α-fluoro Substitution, and its N-methyl-N-phenylDerivatives (Cavalleri et al., 1968):

Hydroxy-Containing Derivatives of Acetamide:

Reported compounds include those where n=0, 1, or 2, R=Me, CF₃, C₇H₁₅,Et, including those with various substitution around the benzene ring(methyl, alkyl, alkoxy, chloro, fluoro, trifluoromethyl), and including3,4-dichlorophenyl derivative, p-bromophenyl, p-fluoro, and p-chloroderivatives. (Choudhury-Mukherjee et al., 2003; Schenck et al., 2004;Lenkowski et al., 2004; Meza-Toledo et al., 2008a; Joseph-Nathan et al.,1978; Meza-Toledo et al., 2004; Sandoval et al., 1995; Meza-Toledo etal., 2008b; Meza-Toledo et al., 1990; Meza-Toledo et al., 1995;Meza-Toledo et al., 1998; Carvajal-Sandoval et al., 1998).

While some of these derivatives are known to have anticonvulsantactivity, none were reported to inhibit neuronal nicotinic acetylcholinereceptors (nAChRs) or be effective in medically refractory epilepsy.

SUMMARY

The present disclosure pertains to orally available aryl-substitutedacetamide and pyrrolidin-2-one derivatives that are effective intreating medically refractory epilepsy and nerve agent poisoning.

Tests of various α-substituted acetamides, lactams, and cyclic imides inrodent models of conventional as well as medically refractory epilepsysuggested that the α-phenyl-substituted acetamide and lactam derivativesexhibit a better spectrum of antiepileptic activity than thecorresponding cyclic imide derivatives. Specifically, theα-phenyl-substituted acetamide and lactam derivatives show a broaderactivity in the models of medically refractory epilepsy.

The present derivatives are distinct from those previously reported orutilized for several reasons. First, they have electronegativesubstituents (F, Cl, I, Br, CF₃, CCl₃, methoxy, methoxy-ethoxy) in thephenyl ring that prevent undesirable metabolic reactions (such asp-hydroxylation) and improve potency and biodistribution. They also lacka hydroxy group in the α-position, which prevents undesirable metabolicreactions (thus producing compounds with better safety margin) andexcessive hydrogen bonding (improving solubility). The achiral nature of2-methyl-2-phenylpropanamide derivatives is also expected to simplifymanufacturing (including quality control), preclinical and clinicaltesting, and therapeutic monitoring in a clinical setting. Unlike manyother compounds, the proposed derivatives have robust activity in rodentmodels of medically refractory (drug-resistant) epilepsy and thus arewell positioned to fill the unmet need of treating medically refractoryepilepsy (which accounts for up to a third of all epilepsy cases).Finally, the derivatives show good oral bioavailability (which is highlybeneficial, since antiepileptic drugs (AEDs) are typically administeredorally).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows previously reported anticonvulsant α-substitutedacetamides, lactams, cyclic imides, and structurally related compounds.

FIG. 2 shows Scheme I, a representative synthetic scheme for exemplarycompounds having anti-seizure activity in accordance with preferredembodiments described herein.

FIG. 3 shows Scheme II, a representative synthetic scheme for exemplarycompounds having anti-seizure activity in accordance with preferredembodiments described herein.

FIG. 4 shows Scheme III, a representative synthetic scheme for exemplarycompounds having anti-seizure activity in accordance with preferredembodiments described herein.

FIG. 5 shows Scheme IV, a representative synthetic scheme for exemplarycompounds having anti-seizure activity in accordance with preferredembodiments described herein.

FIG. 6 shows a synthetic scheme for the preparation of2-methyl-2-phenylpropanamide, in accordance with preferred embodimentsdescribed herein

FIG. 7 shows a synthetic scheme for the preparation of2-methyl-2-(4-(trifluoromethyl)phenyl)propanamide, in accordance withpreferred embodiments described herein.

FIG. 8 shows a synthetic scheme for the preparation of2-methyl-2-(4-fluorophenyl)propanamide, in accordance with preferredembodiments described herein.

FIG. 9 shows a synthetic scheme for the preparation of2-methyl-2-(2-fluorophenyl)propanamide, in accordance with preferredembodiments described herein.

FIG. 10 shows a synthetic scheme for the preparation of2-methyl-2-(2,3,6-trifluorophenyl)propanamide, in accordance withpreferred embodiments described herein.

FIG. 11 shows anti-seizure activity of representative2-methyl-2-phenylpropanamide (2M2PPA) derivatives:2-methyl-2-phenylpropanamide, 2-methyl-2-(2-fluorophenyl)propanamide,2-methyl-2-(3-fluorophenyl)propanamide,2-methyl-2-(4-fluorophenyl)propanamide,2-methyl-2-(2,3,6-trifluorophenyl)propanamide,2-methyl-2-(2-trifluoromethylphenyl)propanamide,2-methyl-2-(3-trifluoromethylphenyl)propanamide,2-methyl-2-(4-trifluoromethylphenyl)propanamide.

FIG. 12 shows activity of racemic 3-ethyl-3-phenylpyrrolidin-2-one inpreventing convulsions in animal models of medically refractoryepilepsy.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present disclosure relates to aryl-substituted acetamide andpyrrolidin-2-one (γ-butyrolactam) derivatives endowed with anti-seizureactivity.

Those skilled in the art will appreciate that some substituentsintroduced in the aromatic ring may have a profound influence onpharmacological potency and ADME of drugs. For example, the introductionof a stable substituent in the para position may prevent metabolicelimination due to enzymatic para-hydroxylation and thus give aderivative with a longer duration of action. In some instances, the samecan be accomplished via the introduction of a stable substituent in themew position, in which case para-hydroxylation is prevented due tosterical hindrance (mismatch between the molecular structure of thesubstituted aromatic ring and the active site of the hydroxylase).

Preferred embodiments include 2-methyl-2-phenylpropanamide,2-phenylbutyramide, and 2-phenylpropanamide derivatives bearing singleor multiple substituents on the aromatic ring and having the formulashown below:

where R₁ and R₂ are each independently selected from the groupconsisting of hydrogen, methyl (CH₃), trifluoromethyl (CF₃),2,2,2-trifluoroethyl (CH₂CF₃), and ethyl (CH₂CH₃), and R₃-R₇ are eachindependently selected from the group consisting of H, F, Cl, Br, I,CF₃, CCl₃, CBr₃, OCH₃, OCH₂CH₂OCH₃, CN, and including anypharmaceutically acceptable salts, co-crystals, or prodrugs thereof.

Additional preferred embodiments include 4-phenylbutyramide derivativesbearing single or multiple substituents in the aromatic ring and havingthe formula shown below:

where R₃-R₇ are each independently selected from the group consisting ofH, F, Cl, Br, I, CF₃, CCl₃, CBr₃, OCH₃, OCH₂CH₂OCH₃, CN, and includingany pharmaceutically acceptable salts, co-crystals, or prodrugs thereof.

Additional preferred embodiments include1-phenylcyclopropane-1-carboxamide derivatives bearing single ormultiple substituents in the aromatic ring and having the formula shownbelow:

where R₁-R₅ are each independently selected from the group consisting ofH, F, Cl, Br, I, CF₃, CCl₃, CBr₃, OCH₃, OCH₂CH₂OCH₃, CN, and includingany pharmaceutically acceptable salts, co-crystals, or prodrugs thereof.

Additional preferred embodiments include pyrrolidin-2-one(γ-butyrolactam) derivatives bearing single or multiple substituents inthe aromatic ring and having the formula shown below:

where R₂ is selected from the group consisting of H, methyl (CH₃),trifluoromethyl (CF₃), 2,2,2-trifluoroethyl (CH₂CF₃), and ethyl(CH₂CH₃), and R₃-R₇ are each independently selected from the groupconsisting of H, F, Cl, Br, I, CF₃, CCl₃, CBr₃, OCH₃, OCH₂CH₂OCH₃, CN,and including any pharmaceutically acceptable salts, co-crystals, orprodrugs thereof.

The present compounds set forth above, alone or in a combination withappropriate carriers/excipients, are useful in preventing, inhibiting,or alleviating convulsive and non-convulsive seizures, such as thoseencountered in epilepsy (including, but not limited to, medicallyrefractory epilepsy) and in nerve agent (including but not limited toorganophosphorus compounds, such as soman, etc.) poisoning.

The exemplary compounds described herein may occur in differentgeometric and enantiomeric forms, and both pure forms and mixtures ofthese separate isomers are included in the scope of this invention, aswell as any physiologically functional or pharmacologically acceptablesalts, co-crystals, or prodrugs thereof. Production of these alternateforms would be well within the capabilities of one skilled in the art.

The current invention also pertains to methods of prevention or seizuresor treatment of epilepsy or treatment of individuals suffering fromseizures, including the step of administering a compound in accordancewith preferred embodiments disclosed herein.

In another aspect of the present invention there is provided apharmaceutical composition including a therapeutically effective amountof a compound that prevents or treats seizures as discussed above and apharmaceutically acceptable excipient, adjuvant, carrier, buffer orstabilizer. A “therapeutically effective amount” is to be understood asan amount of an exemplary compound that is sufficient to show inhibitoryeffects on seizures. The actual amount, rate and time-course ofadministration will depend on the nature and severity of the disease orcondition being treated. Prescription of treatment is within theresponsibility of general practitioners and other medical doctors. Thepharmaceutically acceptable excipient, adjuvant, carrier, buffer orstabiliser should be nontoxic and should not interfere with the efficacyof the active ingredient. The precise nature of the carrier or othermaterial will depend on the route of administration, which may be oral(which is preferred), or by injection, such as cutaneous, subcutaneous,or intravenous injection, or by microneedle delivery, or by patchdelivery, or by dry powder inhaler.

Pharmaceutical compositions for oral administration may be in tablet,capsule, powder or liquid form. A tablet may comprise a solid carrier oran adjuvant. Liquid pharmaceutical compositions generally comprise aliquid carrier such as water, petroleum, animal or vegetable oils,mineral oil or synthetic oil. Physiological saline solution, dextrose orother saccharide solution or glycols such as ethylene glycol, propyleneglycol or polyethylene glycol may be included. A capsule may comprise asolid carrier such as gelatin. For intravenous, cutaneous orsubcutaneous injection, the active ingredient will be in the form of aparenterally acceptable aqueous solution which is pyrogen-free and has asuitable pH, isotonicity and stability. Those of relevant skill in theart are well able to prepare suitable solutions using, for example,isotonic vehicles such as sodium chloride solution, Ringer's solution,or lactated Ringer's solution. Preservatives, stabilizers, buffers,antioxidants and/or other additives may be included as required.

In another aspect, there is provided the use in the manufacture of amedicament of a therapeutically effective amount of an anti-seizure oranti-epileptic compound as defined above for administration to asubject.

The terms “anti-seizure” or “anti-epileptic” as used herein refer to theinhibition, prevention, or treatment of seizures or epilepsy, includingmedically refractory epileptic seizures or seizures caused by nerveagent poisoning.

The term “pharmaceutically acceptable salt” used throughout thespecification is to be taken as meaning any acid or base derived saltformed from hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic,malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic, isoethonic acids and the like, and potassium carbonate,sodium or potassium hydroxide, ammonia, triethylamine, triethanolamineand the like.

The term “co-crystal” used throughout the specification means a solid,crystalline material that includes a drug or a pharmacological substancein the same crystal lattice as an acceptable excipient or othertypically inactive ingredient. (FDA Guidance for Industry—RegulatoryClassification of Pharmaceutical Co-Crystals, April 2013).

The term “prodrug” means a pharmacological substance that isadministered in an inactive, or significantly less active, form. Onceadministered, the prodrug is metabolised in vivo into an activemetabolite.

The term “therapeutically effective amount” means a nontoxic butsufficient amount of the drug to provide the desired therapeutic effect.The amount that is “effective” will vary from subject to subject,depending on the age and general condition of the individual, theparticular concentration and composition being administered, and thelike. Thus, it is not always possible to specify an exact effectiveamount. However, an appropriate effective amount in any individual casemay be determined by one of ordinary skill in the art using routineexperimentation. Furthermore, the effective amount is the concentrationthat is within a range sufficient to permit ready application of theformulation so as to deliver an amount of the drug that is within atherapeutically effective range.

Further aspects of the present invention will become apparent from thefollowing description given by way of example only and with reference tothe accompanying synthetic schemes.

There are multiple approaches suitable for the preparation of compoundshaving the formulas set forth above. FIG. 2 shows Scheme I, or anexemplary synthetic scheme for certain compounds in accordance withpreferred embodiments herein. In Scheme I, target amides can be easilyprepared from the corresponding acids through addition of theintermediate acid chloride to an aqueous solution of ammonia. Some ofsuch acids are available via acid- or base-catalyzed hydrolysis of thecorresponding nitriles or methyl esters. If R is an alkyl substituent,such as methyl or ethyl, both the nitrile and the methyl ester areaccessible through extensive alkylation of the correspondingunsubstituted substrates in presence of an alkylating agent, such asmethyl or ethyl iodide, and a base, such as NaH (Takamatsu et al.,2015). Methyl esters can be prepared from the reaction of correspondingacids with thionyl chloride in methanol. Many of starting nitriles andacids are commercially available at low cost, with diverse substitutionpatterns: fluoro-substituted (including several fluorine atoms,symmetrical and unsymmetrical patterns), trifluoromethyl-substituted,methoxy-, bromo-, and iodo-derivatives, amongst others. Both pathwaysconsist of only a few synthetic steps, and are deemed to be scalable.Some methyl esters are known to be converted directly into primaryamides via a transamination procedure (Bundesmann et al., 2010; Gust etal., 1987). Some gem-dimethyl esters can be alternatively assembled viaPd-catalyzed α-arylation procedure, reported by Hartwig (Jorgensen etal., 2002; Hama et al., 2008), that allows connection of the aryl andaliphatic portion of the target amides. In such cases, commerciallyavailable aryl bromides or chlorides can be used as starting materials,to be coupled with methyl isobutyrate.

FIG. 3 shows Scheme II, an exemplary synthetic scheme for certaincompounds in accordance with preferred embodiments herein. In Scheme II,target amides can be prepared from the corresponding acids throughaddition of the intermediate acid chloride to an aqueous solution ofammonia. Such acids can be prepared from the Wittig reaction ofsubstituted benzaldehydes with ylide derived from3-(triphenylphosphonium)propionic acid bromide (Zhang, X. et al., 2016),or of their homologues with (carbethoxymethylene)triphenylphosphorane(Wang et al., 2001), followed by hydrogenation of the resulting doublebond in either case. While many substituted benzaldehydes arecommercially available, arylacetaldehydes can be easily prepared fromthe corresponding esters via reduction/oxidation (for example, LAHfollowed by Dess-Martin oxidation) sequence (Kolonko et al., 2008).

FIG. 4 shows Scheme III, an exemplary synthetic scheme for certaincompounds in accordance with preferred embodiments herein. In SchemeIII, target lactams can be prepared from aryl acetic esters: α-methyl orα-ethyl substituted, or unsubstituted. Their deprotonation with lithiumdiisopropylamide, followed by addition of commercially available bromo-or chloroacetonitrile, can install the necessary two-carbon fragment(WO2007/127763). The nitrile can be reduced to an amino group byreported procedure and following cyclization in situ should yield thedesired lactams (Doherty et al., 2012; Reddy et al., 1996).Alternatively, the two carbon-fragment can be installed via Michaeladdition of nitroethylene to the starting ester (Flintoft et al., 1999),and the reduction (Nilsson et al., 1992; Bousquet et al., 2015) of thenitro group followed by lactamization in situ should provide the desiredtarget substrates. The starting materials, esters, can be prepared viaclassic malonic ester synthesis or by monoalkylation of thecorresponding aryl acetic esters (Kato et al., 2003).

Additionally, unalkylated aryl-lactams can be prepared by Michaeladdition of nitromethane to alkenyl esters (Yin et al., 2015; Jiang etal., 2012), followed by reduction of the nitro group and lactamization(Scheme IV), as shown in Scheme IV in FIG. 5 . Alkenyl esters can beprepared via aldol condensation of aryl acetic esters with formaldehyde(Zhu et al., 2017).

Example 1. Synthesis

FIG. 6 shows a synthetic scheme for the preparation of2-methyl-2-phenylpropanamide.

Methyl ester formation. Thionyl chloride, 10.60 mL (2.0 equiv, 0.146mol), was added dropwise to a mixture of 10.00 g of phenylacetic acid(73.4 mmol) in 40 mL methanol at 0° C. After 10 min of stirring, themixture was brought to a reflux. Upon completion of the reaction (5 h,control by TLC), the reaction mixture was cooled to room temperature andconcentrated to ˜15 mL. The mixture was transferred to 40 mL ofsaturated NaHCO₃ solution and extracted with dichloromethane (3×20 mL).Combined organic fractions were washed with brine (30 mL), filteredthrough cotton and concentrated under reduced pressure to yield 9.84 g(65.5 mmol) of a methyl 2-phenylacetate, clear liquid (89%).

Dimethylation. A solution of methyl 2-phenylacetate (2.01 g, 13.4 mmol)and methyl iodide (2.08 mL, 33.5 mmol, 2.5 equiv) in anhydrous THF (15mL) was treated portionwise with sodium hydride (60% suspension inmineral oil, 1.18 g, 29.5 mmol, 2.2 equiv) at 0° C., warmed to roomtemperature and reacted for 24 h. The reaction mixture was transferredinto a separatory funnel with ice/water and acidified with 1.0 M HCl (30mL). The product was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed brine (30 mL), filtered throughcotton, and concentrated under reduced pressure to yield dark oil whichwas purified by flash chromatography (hexanes/ethyl acetate) to provide2.26 g of methyl 2-methyl-2-phenylpropanoate, yellow oil (12.7 mmol,95%).

Ester hydrolysis. Methyl 2-methyl-2-phenylpropanoate (0.840 g, 4.71mmol) was dissolved in 5 mL of 1,4-dioxane and 10 mL of 1.0 M NaOH (10.0mmol, 2.1 equiv) was added. The mixture was heated at 95° C. for 24 h.20 mL of 1.0 M HCl was added and the mixture was extracted withdichloromethane (3×20 mL). Combined organic fractions were washed withbrine (30 mL), filtered through cotton and concentrated under reducedpressure to yield a crude mixture which was purified by flashchromatography (hexanes/ethyl acetate), 0.758 g of2-methyl-2-phenylpropanoic acid (4.62 mmol, 98%).

Amide formation. 1.26 mL of oxalyl chloride (14.70 mmol, 3.2 equiv) wasadded dropwise to the solution of 0.750 g (4.57 mmol) of2-methyl-2-phenylpropanoic acid in 10 mL dichloromethane at 0° C. Thiswas followed by the addition of 1 drop of DMF. The reaction mixture wasbrought to room temperature, and after 9 hours of stirring was slowlyadded to 20 mL of 30% aqueous NH₃ solution upon vigorous stirring. Thestirring continued for 9 more hours. The reaction mixture diluted withwater (20 mL), filtered from white precipitate into a separatory funnel,and washed with dichloromethane (3×30 mL). Combined organic fractionswere washed with brine (30 mL), filtered through cotton and concentratedunder reduced pressure to yield a crude amide, which was purified byflash chromatography (hexanes/ethyl acetate), 0.588 g of2-methyl-2-phenylpropanamide (3.60 mmol, 78% yield). Melting point:162.0° C.

FIG. 7 shows a synthetic scheme for the preparation of2-methyl-2-(4-(trifluoromethyl)phenyl)propanamide.

Methyl Ester formation. Thionyl chloride, 3.48 mL (2.0 equiv, 48.0mmol), was added dropwise to a mixture of 4.96 g (24.3 mmol) of2-(4-(trifluoromethyl) phenyl)acetic acid in 40 mL methanol at 0° C.After 10 min of stirring, the mixture was brought to a reflux. Uponcompletion of the reaction (8 h, control by TLC), the reaction mixturewas cooled to room temperature and concentrated to ˜10 mL. The mixturewas transferred to 40 mL of saturated NaHCO₃ solution and extracted withdichloromethane (3×20 mL). Combined organic fractions were washed withbrine (30 mL), filtered through cotton and concentrated under reducedpressure to yield 5.09 g (23.3 mmol) of methyl2-(4-(trifluoromethyl)phenyl)acetate, clear liquid (96%).

Dimethylation and hydrolysis. A solution of methyl2-(4-(trifluoromethyl)phenyl)acetate (5.09 g, 23.3 mmol) and methyliodide (3.79 mL, 60.9 mmol, 2.6 equiv) in anhydrous THF (25 mL) wastreated portionwise with sodium hydride (60% suspension in mineral oil,2.15 g, 53.8 mmol, 2.3 equiv) at 0° C., warmed to room temperature andreacted for 24 h. The reaction mixture was transferred into a separatoryfunnel with ice/water and acidified with 1.0 M HCl (30 mL). The productwas extracted with ethyl acetate (3×30 mL). The combined organic layerswere washed brine, filtered through cotton, and concentrated underreduced pressure to yield dark oil. Unpurified dimethylated product wasdissolved in 16 mL of 1,4-dioxane and 8 mL of 6.0 M NaOH (48.0 mmol, 2.1equiv) was added. The mixture was heated at 95° C. for 24 h. 30 mL of3.0 M HCl was added and the mixture was extracted with dichloromethane(3×20 mL). Combined organic fractions were washed with brine (30 mL),filtered through cotton and concentrated under reduced pressure to yielda crude mixture which was purified by flash chromatography(hexanes/ethyl acetate), 4.42 g of2-methyl-2-(4-(trifluoromethyl)phenyl)propanoic acid (19.0 mmol, 82%over two steps).

Amide formation. 3.00 mL of oxalyl chloride (35.0 mmol, 2.0 equiv) wasadded dropwise to the solution of 4.021 g (17.3 mmol) of2-methyl-2-(4-(trifluoromethyl)phenyl)propanoic acid in 35 mLdichloromethane at 0° C. This was followed by the addition of 2 drops ofDMF. The reaction mixture was brought to room temperature, and after 9hours of stirring was slowly added to 60 mL of chilled 30% aqueous NH₃solution upon vigorous stirring. The stirring continued for 9 morehours. The reaction mixture was diluted with water (30 mL), filteredfrom white precipitate into a separatory funnel, and washed withdichloromethane (3×30 mL). Combined organic fractions were washed withbrine (20 mL), filtered through cotton and concentrated under reducedpressure to yield a crude amide, 3.950 g.2-Methyl-2-(4-(trifluoromethyl)phenyl)propanamide was recrystallizedfrom anhydrous ethanol. White crystals, 3.133 g (78%). Melting point:143.9° C.

FIG. 8 shows a synthetic scheme for the preparation ofmethyl-2-(4-fluorophenyl)propanamide.

Methyl ester formation. Thionyl chloride, 4.70 mL (2.0 equiv, 64.8mmol), was added dropwise to a mixture of 5.01 g (32.5 mmol) of2-(4-fluorophenyl)acetic acid in 40 mL methanol at 0° C. After 10 min ofstirring, the mixture was brought to a reflux. Upon completion of thereaction (8 h, control by TLC), the reaction mixture was cooled to roomtemperature and concentrated to ˜10 mL. Mixture was transferred to 40 mLof saturated NaHCO₃ solution and extracted with dichloromethane (3×20mL). Combined organic fractions were washed with brine (30 mL), filteredthrough cotton and concentrated under reduced pressure to yield 5.28 g(31.4 mmol) of methyl 2-(4-fluorophenyl)acetate, clear liquid (97%).

Dimethylation and hydrolysis. A solution of methyl2-(4-fluorophenyl)acetate (5.28 g, 31.4 mmol) and methyl iodide (4.89mL, 78.5 mmol, 2.5 equiv) in anhydrous THF (25 mL) was treatedportionwise with sodium hydride (60% suspension in mineral oil, 2.78 g,69.5 mmol, 2.2 equiv) at 0° C., warmed to room temperature and reactedfor 24 h. The reaction mixture was transferred into a separatory funnelwith ice/water and acidified with 1.0 M HCl (30 mL). The product wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed brine, filtered through cotton, and concentrated under reducedpressure to yield dark oil. Unpurified dimethylated product wasdissolved in 15 mL of 1,4-dioxane and 14 mL of 6.0 M NaOH (84.0 mmol,2.7 equiv) was added. The mixture was heated at 95° C. for 24 h. 40 mLof 3.0 M HCl was added and the mixture was extracted withdichloromethane (3×20 mL). Combined organic fractions were washed withbrine (30 mL), filtered through cotton and concentrated under reducedpressure to yield a crude mixture which was purified by flashchromatography (hexanes/ethyl acetate), 5.36 g of2-methyl-2-(4-fluorophenyl)propanoic acid (29.4 mmol, 94% over twosteps).

Amide formation. 4.00 mL of oxalyl chloride (46.7 mmol, 1.6 equiv) wasadded dropwise to the solution of 5.329 g (29.2 mmol) of2-methyl-2-(4-fluorophenyl)propanoic acid in 30 mL dichloromethane at 0°C. This was followed by the addition of 2 drops of DMF. The reactionmixture was brought to room temperature, and after 9 hours of stirringwas slowly added to 60 mL of chilled 30% aqueous NH₃ solution uponvigorous stirring. The stirring continued for 9 more hours. The reactionmixture was diluted with water (30 mL), filtered from white precipitateinto a separatory funnel, and washed with dichloromethane (3×30 mL).Combined organic fractions were washed with brine (20 mL), filteredthrough cotton and concentrated under reduced pressure to yield a crudeamide, 5.365 g. 2-Methyl-2-(4-fluorophenyl)propanamide wasrecrystallized from anhydrous ethanol. White crystals, 3.993 g (75%).Melting point: 130.7° C.

FIG. 9 shows a synthetic scheme for the preparation of2-methyl-2-(2-fluorophenyl)propanamide.

Methyl Ester formation. Thionyl chloride, 5.64 mL (2.0 equiv, 77.74mmol), was added dropwise to a mixture of 5.990 g (38.87 mmol) of2-(2-fluorophenyl)acetic acid in 40 mL methanol at 0° C. After 10 min ofstirring, the mixture was brought to a reflux. Upon completion of thereaction (8 h, control by TLC), the reaction mixture was cooled to roomtemperature and concentrated to ˜10 mL. The mixture was transferred to40 mL of saturated NaHCO₃ solution and extracted with dichloromethane(3×20 mL). Combined organic fractions were washed with brine (30 mL),filtered through cotton and concentrated under reduced pressure to yield6.373 g (37.89 mmol) of methyl 2-(2-fluorophenyl)acetate, clear liquid(97%).

Dimethylation and hydrolysis. A solution of methyl2-(2-fluorophenyl)acetate (6.373 g, 37.89 mmol) and methyl iodide (5.90mL, 94.8 mmol, 2.5 equiv) in anhydrous THF (25 mL) was treatedportionwise with sodium hydride (60% suspension in mineral oil, 3.32 g,83.0 mmol, 2.2 equiv) at 0° C., warmed to room temperature and reactedfor 24 h. The reaction mixture was transferred into a separatory funnelwith ice/water and acidified with 1.0 M HCl (30 mL). The product wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed brine, filtered through cotton, and concentrated under reducedpressure to yield light yellow oil. The oil was dissolved in 16 mL of1,4-dioxane and 19.0 mL of 6.0 M NaOH (113.7 mmol, 3.0 equiv) was added.The mixture was heated at 95° C. for 24 h. 30 mL of 3.0 M HCl was addedand the mixture was extracted with dichloromethane (3×20 mL). Combinedorganic fractions were washed with brine (30 mL), filtered throughcotton and concentrated under reduced pressure to yield a crude mixturewhich was purified by flash chromatography (hexanes/ethyl acetate),5.799 g of 2-methyl-2-(2-fluorophenyl)propanoic acid (31.83 mmol, 84%over two steps).

Amide formation. 5.44 mL of oxalyl chloride (63.4 mmol, 2.0 equiv) wasadded dropwise to the solution of 5.776 g (31.70 mmol) of2-methyl-2-(2-fluorophenyl)propanoic acid in 35 mL dichloromethane at 0°C. This was followed by the addition of 2 drops of DMF. The reactionmixture was brought to room temperature, and after 9 hours of stirringwas slowly added to 60 mL of chilled 30% aqueous NH₃ solution uponvigorous stirring. The stirring continued for 9 more hours. The reactionmixture was diluted with water (30 mL), filtered from white precipitateinto a separatory funnel, and washed with dichloromethane (3×30 mL).Combined organic fractions were washed with brine (20 mL), filteredthrough cotton and concentrated under reduced pressure to yield a crudeamide. 2-Methyl-2-(2-fluorophenyl)propanamide was purified via columnchromatography (hexanes/ethyl acetate) and additionally recrystallizedfrom MeOH/water. White crystals, 5.342 g (29.48 mmol, 93%). Meltingpoint: 95.9° C.

FIG. 10 shows a synthetic scheme for the preparation of2-methyl-2-(2,3,6-trifluorophenyl)propanamide.

Methyl Ester formation. Thionyl chloride, 3.79 mL (2.0 equiv, 52.3mmol), was added dropwise to a mixture of 4.970 g (26.15 mmol) of2-(2,3,6-trifluorophenyl)acetic acid in 40 mL methanol at 0° C. After 10min of stirring, the mixture was brought to a reflux. Upon completion ofthe reaction (8 h, control by TLC), the reaction mixture was cooled toroom temperature and concentrated to ˜10 mL. The mixture was transferredto 40 mL of saturated NaHCO₃ solution and extracted with dichloromethane(3×20 mL). Combined organic fractions were washed with brine (30 mL),filtered through cotton and concentrated under reduced pressure to yield5.123 g (25.10 mmol) of methyl 2-(2,3,6-trifluorophenyl)acetate, clearliquid (96%).

Dimethylation and hydrolysis. A solution of methyl2-(2,3,6-trifluorophenyl)acetate (5.091 g, 24.94 mmol) and methyl iodide(3.89 mL, 62.46 mmol, 2.5 equiv) in anhydrous THF (25 mL) was treatedportionwise with sodium hydride (60% suspension in mineral oil, 2.20 g,55.05 mmol, 2.2 equiv) at 0° C., warmed to room temperature and reactedfor 24 h. The reaction mixture was transferred into a separatory funnelwith ice/water and acidified with 1.0 M HCl (30 mL). The product wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed brine, filtered through cotton, and concentrated under reducedpressure to yield light yellow oil. The oil was dissolved in 16 mL of1,4-dioxane and 12.5 mL of 6.0 M NaOH (74.82 mmol, 3.0 equiv) was added.The mixture was heated at 95° C. for 24 h. 30 mL of 3.0 M HCl was addedand the mixture was extracted with dichloromethane (3×20 mL). Combinedorganic fractions were washed with brine (30 mL), filtered throughcotton and concentrated under reduced pressure to yield a crude mixturewhich was purified by flash chromatography (hexanes/ethyl acetate),4.353 g of 2-methyl-2-(2,3,6-trifluorophenyl)propanoic acid (19.95 mmol,80% over two steps).

Amide formation. 3.42 mL of oxalyl chloride (39.86 mmol, 2.0 equiv) wasadded dropwise to the solution of 4.348 g (19.93 mmol) of2-methyl-2-(2,3,6-trifluorophenyl)propanoic acid in 35 mLdichloromethane at 0° C. This was followed by the addition of 2 drops ofDMF. The reaction mixture was brought to room temperature, and after 9hours of stirring was slowly added to 60 mL of chilled 30% aqueous NH₃solution upon vigorous stirring. The stirring continued for 9 morehours. The reaction mixture was diluted with water (30 mL), filteredfrom white precipitate into a separatory funnel, and washed withdichloromethane (3×30 mL). Combined organic fractions were washed withbrine (20 mL), filtered through cotton and concentrated under reducedpressure to yield a crude amide.2-Methyl-2-(2,3,6-trifluorophenyl)propanamide was purified via silicacolumn chromatography (hexanes/ethyl acetate) and additionallyrecrystallized from MeOH/water. White crystals, 3.203 g (14.75 mmol,74%). Melting point: 104.6° C.

Example 2. Activity

Anti-seizure activity of representative 2-methyl-2-phenylpropanamide(2M2PPA) derivatives was investigated in mice. The testing protocol wasspecifically designed to find orally bioavailable compounds activeagainst medically refractory epilepsy. Representative compounds thatwere tested had the formula shown below with the substitutions providedin FIG. 11 .

In the representative compounds that were tested, R₁ and R₂ were Me. Anysubstituents not explicitly specified on the phenyl ring were H. Forexample, in FIG. 11 , 2-F refers to the above structure where R₃ is F,R₁ is Me, R₂ is Me, and R₄, R₅, R₆, and R₇ are all H. Representativecompounds included 2-methyl-2-phenylpropanamide,2-methyl-2-(2-fluorophenyl)propanamide,2-methyl-2-(3-fluorophenyflpropanamide,2-methyl-2-(4-fluorophenyl)propanamide,2-methyl-2-(2,3,6-trifluorophenyl)propanamide,2-methyl-2-(2-trifluoromethylphenyl)propanamide,2-methyl-2-(3-trifluoromethylphenyepropanamide, and2-methyl-2-(4-trifluoromethylphenyl)propanamide.

The derivatives identified in FIG. 11 were tested at the EpilepsyTherapy Screening Program, a component of the National Institute ofNeurological Disorders and Stroke (NINDS), Rockville, Md., for theirability to protect mice against seizures produced by 6 Hz (44 mA)stimulation. The compounds suspended in PEG/Tween solution wereadministered orally to adult male C57BL/6 mice at a dose of 0.61 mmol/kgof body mass in a volume of 0.01 mL/g of body weight. The seizurechallenge was performed either 0.5 h or 4 hours after administration.The animal studies were conducted in accordance with federal and Stateof Utah regulations using protocols approved by the University of UtahInstitutional Animal Care and Use Committee (IACUC).

In the MES test (carried out as described by Krall et al., 1978), 50 mAcurrent (60 Hz) was delivered for 2 s through corneal electrodes, andthe animals were observed for the presence of tonic-clonic seizures.This test is a good model of motor (grand mal) seizures in humans.

In the 6 Hz (44 mA) test (carried out as described by Barton et al.,2001), 42 mA current (6 Hz) was delivered for 3 s through cornealelectrodes, and the animals were observed for the presence of seizures.This test is a good model of medically refractory psychomotor seizuresin humans.

The results in FIG. 11 demonstrate that various representative2-methyl-2-phenylpropanamide derivatives were effective in protectingmice from seizures upon oral administration. Additional resultsdemonstrate that structurally similar compounds having the formulasidentified above have similar activity. Indeed, data provided in FIG. 12indicates that 3-ethyl-3-phenylpyrrolidin-2-one is active in multiplerodent models of medically refractory epilepsy.

REFERENCES

The following documents and publications are hereby incorporated byreference.

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What is claimed is:
 1. A compound capable of reducing the risk ofseizures resulting from epilepsy or nerve agent poisoning and having astructure of:

wherein R₃, R₄, and R₇ are F, R₁ and R₂ are CH₃, and R₅ and R₆ are H;and pharmaceutically acceptable salts, co-crystals, and prodrugsthereof.
 2. A pharmaceutical composition for reducing the risk ofseizures resulting from epilepsy or nerve agent poisoning comprising atherapeutically effective amount of the compound of claim 1 and apharmaceutically acceptable excipient, adjuvant, carrier, buffer,stabilizer, or mixture thereof.
 3. A method of reducing the risk ofseizures resulting from epilepsy in a patient in need thereof comprisingadministering the pharmaceutical composition of claim
 2. 4. A method ofreducing the risk of seizures resulting from nerve agent poisoning in apatient in need thereof comprising administering the pharmaceuticalcomposition of claim 2.